Benzyl esters of benzofuran-2-carboxylic acids useful as inhibitors of leukotriene biosynthesis

ABSTRACT

Compounds of the Formula I: ##STR1## and pharmaceutically acceptable salts thereof are inhibitors of leukotriene biosynthesis. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. These compounds are thus useful in the treatment of asthma, allergic disorders, inflammation, skin diseases and certain cardiovascular disorders.

This is a division of application Ser. No. 725,265, filed Apr. 19, 1985,now U.S. Pat. No. 4,663,347, which application is a continuation-in-partof U.S. Ser. No. 661,645, filed Oct. 17, 1984 now abandoned, which is acontinuation-in-part of U.S. Ser. No. 547,508, filed Oct. 31, 1983, nowabandoned.

This invention is directed to pharmaceutical compositions containing acompound of the Formula I: ##STR2## and pharmaceutically acceptablesalts thereof wherein the various subtituents are as defined hereinbelow.

This invention also provides a method of treatment for disease statescaused by the synthesis of the Leukotrienes C₄, D₄, E₄ and F₄, as wellas Leukotriene B₄, in mammals especially in a human subject. This methodcomprises administering to said subject an effective amount of acompound of Formula I combined with an appropriate pharmaceuticalcarrier.

The compounds of Formula I may be used to treat or prevent mammalian(especially human) disease states such as erosive gastritis; erosiveesophagitis; inflammatory bowel disease; ethanol-induced hemorrhagicerosions; hepatic ischemia; noxious agent induced damage or necrosis ofhepatic, pancreatic, renal, or myocardial tissue; liver parenchymaldamage caused by hepatoxic agents such as CCl₄ and D-galactosamine;ischemic renal failure; disease-induced hepatic damage; bile saltinduced pancreatic or gastric damage; trauma- or stress-induced celldamage; and glycerol-induced renal failure.

Finally, this invention also provides novel compounds within the FormulaI that act as inhibitors of the mammalian 5-lipoxygenase enzyme system,thus preventing the biosynthesis of the Leukotrienes C₄, D₄ and E₄ andalso Leukotriene B₄.

U.S. Pat. No. 4,663,347 (Atkinson, et al.,) is incorporated herein byreference in its entirety.

What is claimed is:
 1. A compound of the Formula Id: ##STR3## wherein R₁is hydrogen, C₁ to C₆ alkyl, Ar₁ -C₁ to C₃ alkyl, Ar₁ or CH₂ OH;R₃, R₄and T are each independently selected from:(1) hydrogen; (2) alkylhaving 1 to 4 carbon atoms; (3) alkenyl having 2 to 4 carbon atoms; (4)--(CH₂)_(n) M wherein n is 0 or 1, and M is(a) --OR₅ ; (b) halogen; (c)--CF₃ ; (d) --SR₅ ; (e) Ar₁ ; (f) --COOR₆ ; (g) ##STR4## wherein R₁₂ isH, C₁ to C₆ alkyl, or Ar₁ ; (h) ##STR5## (i) ##STR6## (j) ##STR7## (k)##STR8## (l) NR₈ R₉ ; (m) --NHSO₂ R₁₀ wherein R₁₀ is C₁ to C₆ alkyl,phenyl, p-tolyl or CF₃ ; (n) --SOR₅ ; (o) --CONR₈ R₉ ; (p) --SO₂ NR₈ R₉; (q) --SO₂ R₅ ; (r) --NO₂ ; or (s) --CN; or any two of R₃, R₄ and T maybe joined to form a saturated ring having 5 or 6 ring atoms, said ringatoms comprising 0, 1 or 2 oxygen atoms, the remaining ring atoms beingcarbon; each R₅ is independently H, C₁ to C₆ alkyl, benzyl, Ar₁,perfluoro-C₁ -C₄ alkyl, CH₂ -R₁₁ wherein R₁₁ is C₁ to C₅alkyldimethylamino, hydroxy C₂ to C₅ alkyl, CH₂ COOR₆, or CH₂ CO--R₇ ;each R₆ is independently H or C₁ to C₆ alkyl; each R₇ is indenpendentlyC₁ to C₆ alkyl, benzyl, Ar₁, NR₈ R₉, NHAr₁, or O--C₁ to C₄ alkyl; eachR₈ and each R₉ is independently H or C₁ to C₄ alkyl, or R₈ and R₉ may bejoined through the N to which they are attached to form aheterocycloalkyl ring having 5 to 8 ring atoms; and each Ar₁ isindependently 1- or 2-naphthyl, phenyl or mono- or disubstituted phenyl,wherein the substituents on the phenyl are independently selected fromC₁ to C₃ alkyl, I, Br, Cl, F, COOR₆, (CH₂)_(n) --NR₈ R₉ wherein n is 0to 2, methylenedioxy, C₁ to C₃ alkoxy, OH, CN, NO₂, CF₃, C₁ to C₄ acyl,NR₈ R₉, S--C₁ to C₆ alkyl, SO--C₁ to C₆ alkyl, and SO₂ --C₁ to C₆ alkyl;with the proviso that at least one of R₃, R₄ or T is either OR₅ or--OCOR₇ ;or a pharmaceutically acceptable salt thereof.
 2. A compound ofFormula I ##STR9## wherein the compound is selected from the followinggroup:

    __________________________________________________________________________    Compound                                                                            R.sub.1                                                                          R.sub.2    R.sub.3 R.sub.4  T.sup.c                                  __________________________________________________________________________    223   CH.sub.3                                                                         OCH.sub.2 Php-OMe                                                                         ##STR10##                                                                            H        H                                        224   CH.sub.3                                                                         OCH.sub.2 Php-Cl                                                                          ##STR11##                                                                            H        H                                        232   CH.sub.3                                                                         OCH.sub.2 Ph3,4-Cl.sub.2                                                                  ##STR12##                                                                            H        H                                        233   CH.sub.3                                                                         OCH.sub.2 Ph3,4-Cl.sub.2                                                                 4-OAc   H        H                                        234   CH.sub.3                                                                         OCH.sub.2 Ph                                                                              ##STR13##                                                                            5-CH.sub.2 CHCH.sub.2                                                                  H                                        235   CH.sub.3                                                                         OCH.sub.2 Ph                                                                              ##STR14##                                                                            H        H                                        239   CH.sub.3                                                                         OCH.sub.2 Php-Cl                                                                         4-OAc   H        H                                        240   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OAc   H        H                                        255   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    H        H                                        256   CH.sub.3                                                                         OCH.sub.2 Ph3,4-Cl.sub.2                                                                 4-OH    H        H                                        257   CH.sub.3                                                                         OCH.sub.2 Php-Cl                                                                         4-OH    H        H                                        258   CH.sub.3                                                                         OCH.sub.2 Php-OMe                                                                        4-OH    H        H                                        275   CH.sub.3                                                                         OCH.sub.2 Php-F                                                                          5-OH    6-OH     H                                        276   CH.sub.3                                                                         OCH.sub.2 Php-Cl                                                                         5-OH    6-OH     H                                        277   CH.sub.3                                                                         OCH.sub.2 Php-OCH.sub.3                                                                  5-OH    6-OH     H                                        280   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    5-CH.sub.2 SCH.sub.3                                                                   H                                        290   CH.sub.3                                                                         OCH.sub.2Php-OMe                                                                         4-OAc   H        H                                        292   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    7-OH     H                                        293   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OAc   7-OAc    H                                        294   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    7-OH     5-CH.sub.2 CH.sub.2 CH.sub.3             295   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OAc   7-OAc    5-CH.sub.2 CH.sub.2 CH.sub.3             333   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             H       H        .sup.c                                   334   CH.sub.3                                                                         OCH.sub.2 Php-OMe                                                                        H       H        .sup.c                                   335   CH.sub.3                                                                         OCH.sub.2 Php-Cl                                                                         H       H        .sup.c                                   364   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             5-CH.sub.2 CH.sub.2 CH.sub.3                                                          H        .sup.c                                   368   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    5-CH.sub.2 CH.sub.2 CH.sub.3                                                           7-F                                      369   CH.sub.3                                                                         OCH.sub.2 Ph                                                                             4-OH    5-CH.sub.2 CH.sub.2 CH.sub.3                                                           7-Cl                                     __________________________________________________________________________     .sup.c In compounds 223 to 295, V is H; in compounds 333 to 364 T and V       are located at positions 4 and 7 respectively and are both simultaneously     OH, OCOCH.sub.3 or OCO.sub.2 CH.sub.3.                                   


3. A compound of claim 2 which is: 223, 224, 232-235, 239, 240, 255,256, 258, 290, 333, 364, 368, or
 369. 4. A compound of claim 2 which is:333, 364, 368, or
 369. 5. A method of inhibiting mammalian leukotrienebiosynthesis or action which comprises administering to a mammal apharmaceutically effective amount of a compound of claim
 2. 6. A methodof claim 5 wherein the mammal is a human.
 7. A method of treatingpulmonary conditions, inflammation, allergies, pain, cardiovascularconditions, or skin conditions which comprises administering to a humanin need of such treatment a pharmaceutically effective amount of acompound of claim
 2. 8. A pharmaceutical composition useful forinhibiting the biosynthesis of mammalian leukotrienes comprising apharmaceutically acceptable carrier and an effective amount of acompound of claim
 2. 9. A composition of claim 8, wherein the compoundis: 223, 224, 232-235, 239, 240, 255, 256, 258, 290, 333, 364, 368, or369.
 10. A composition of claim 8, wherein the compound is: 255, 333,364, 368, or
 369. 11. A method of inhibiting mammalian leukotrienebiosynthesis or action which comprises administering to a mammalpharmaceutically effective amount of a composition of claim
 8. 12. Amethod of claim 11 wherein the mammal is a human.
 13. A method oftreating pulmonary conditions, inflammation, allergies, pain,cardiovascular conditions, or skin conditions which comprisesadministering to a human in need of such treatment a pharmaceuticallyeffective amount of a composition of claim
 8. 14. A pharmaceuticalcomposition according to claim 8 additionally comprising an effectiveamount of a second active ingredient selected from the group consistingof non-steriodal anti-inflammatory drugs; peripheral analgesic agents;cyclooxygenase inhibitors; leukotriene antagonists; antihistaminicagents; prostaglandin antagonists; and thromboxane antagonists.
 15. Apharmaceutical composition according to claim 14, wherein the secondactive ingredient is a non-steroidal anti-inflammatory drug.
 16. Apharmaceutical composition according to claim 15, wherein saidnon-steroidal anti-inflammatory drug is indomethacin.
 17. Apharmaceutical composition according to claim 8 additionally comprisingan effective amount of a second active ingredient selected from thegroup consisting of non-steriodal anti-inflammatory drugs; peripheralanalgesic agents; cyclooxygenase inhibitors; leukotriene antagonists;antihistaminic agents; prostaglandin antagonists; and thromboxaneantagonists, wherein the weight ratio of the compound described in claim8 to said second active ingredient ranges from about 1000:1 to 1:1000.18. A pharmaceutical composition according to claim 17, wherein theweight ratio ranges from about 200:1 to 1:200.
 19. A pharmaceuticalcomposition according to claim 17, wherein the second active ingredientis a non-steroidal anti-inflammatory drug.
 20. A pharmaceuticalcomposition according to claim 19, wherein the non-steroidalanti-inflammatory drug is indomethacin.